A. Field of Invention
This invention pertains to an improved method for manufacture of 2-oxoimidazolidines of Formula I. In Formula I, R7, R8 and R9 represent one or more substituent bonded to the available carbon atoms on the corresponding ring. Such compounds are useful intermediates in the manufacture of Pramiconazole and structurally related molecules.

B. Description of the Related Art
Pramiconazole is undergoing clinical evaluation for the treatment of seborrheic dermatitis and other fungal skin infections in humans. The 2-oxoimidazolidine ring of this drug is a requisite structural component for anti-fungal activity.

Pramiconazole may be produced efficiently through a convergent chemical synthesis from (2S-cis)-1-[[2-(bromomethyl)-4-(2,4-difluorophenyl)-1,3-dioxolan-4-yl]methyl]-1H-1,2,4-triazole and a 2-oxoimidazolidine of Formula Ia. The latter compound is a unique member of the assemblage of Formula I; wherein R1 is isopropyl; R2, R3, R4, R5, R6, R7, R8 and R9 are hydrogen. As a result of the favorable clinical indications of Pramiconazole and structurally related drugs, there is an interest in methods that may provide a 2-oxoimidazolidine of Formula I more cost effectively relative to the prior art.

To date, the compound of Formula Ia may be most capably prepared in six processing steps comprised of (i) a reaction of 1-(4-methoxyphenyl)piperazine with 1-chloro-4-nitrobenzene, (ii) a reduction of the nitro group of the product obtained from the first step, (iii) a condensation of the aniline derivative attained in the second step with phenyl chloroformate, (iv) a reaction of the phenylcarbamate acquired from the third step with N-(2,2-dimethoxyethyl)-2-propaneamine, (v) a hydrogenation of the double bond of the 2H-imidazol-2-one intermediate gained from the fourth step, and (vi) protolytic cleavage of the methoxy group in the product obtained from the fifth step. Aspects that may restrict the utility of this method in large-scale manufacture of a compound of Formula Ia include the lengthy and time intensive nature of the process, a modest overall product yield, the need to separately produce the specialty amine for the fourth step, the potential for trace heavy metal contamination carrying over into the drug substance from the fifth step, and the formation of a difficult-to-remove process impurity that may negatively impact the quality of the drug substance.
Alternatively, a compound of Formula Ia may be prepared by the reaction of 1-(4-aminophenyl)-3-(1-methylethyl)-2-oxoimidazolidine with N,N-bis(2-chloro-ethyl)-4-methoxybenzenamine followed by a protolytic cleavage of the methoxy group. The 2-oxoimidazolidine intermediate for this method may be obtained in four additional processing steps consisting of (i) an N-alkylation of 4-nitroaniline with 2-bromoethanamine, (ii) acylation of the N-aryl-1,2-ethanodiamine attained from the first step with 1,1′-carbonyldiimidazole, (iii) N-alkylation of the 2-oxoimidazolidine gained from the second step with isopropyl bromide, and (iv) catalytic reduction of the aryl nitro group in the product achieved from the third step. Aspects that may limit the commercial utility of this method include a lengthy sequence of processing operations, the potential for trace heavy metal contamination carrying over from the fourth step into the drug substance, a modest overall yield, and a higher cost of manufacture relative to the process described above.
Moreover, Pramiconazole and certain analogues may be prepared by the reaction of 4-[4-(4-aminophenyl)-1-piperazinyl]phenol with a 1-aryl-2-heteroarylmethyl)-1,3-dioxolan-4-ylmethyl sulfonate or a 2-(halomethyl)-4-(aryl)-1,3-dioxolan-4-yl]methyl]heteroaryl. Thereafter, the 2-oxoimidazolidine ring may be fabricated into the molecule; adding to the number of processing steps of this method. A linear synthetic strategy may amplify manufacturing cost and provide a lower product yield relative to a convergent synthesis of the same compound. As a result, this method of producing a complex 2-oxoimidazolidine may be even less attractive from a commercial perspective than either of the convergent processes described above.
The present invention describes an improved method for the preparation of 2-oxoimidazolidines of Formula I. Such compounds are useful intermediates in the manufacture of Pramiconazole and structurally related compounds.